CDC-48/p97 Coordinates CDT-1 Degradation with GINS Chromatin Dissociation to Ensure Faithful DNA Replication

Andre Franz, Michael Orth, Paul A. Pirson, Remi Sonneville, J. Julian Blow, Anton Gartner, Olaf Stemmann, Thorsten Hoppe

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    Abstract

    Faithful transmission of genomic information requires tight spatiotemporal regulation of DNA replication factors. In the licensing step of DNA replication, CDT-1 is loaded onto chromatin to subsequently promote the recruitment of additional replication factors, including CDC-45 and GINS. During the elongation step, the CDC-45/GINS complex moves with the replication fork; however, it is largely unknown how its chromatin association is regulated. Here, we show that the chaperone-like ATPase CDC-48/p97 coordinates degradation of CDT-1 with release of the CDC-45/GINS complex. C. elegans embryos lacking CDC-48 or its cofactors UFD-1/NPL-4 accumulate CDT-1 on mitotic chromatin, indicating a critical role of CDC-48 in CDT-1 turnover. Strikingly, CDC-48(UFD-1/NPL-4)-deficient embryos show persistent chromatin association of CDC-45/GINS, which is a consequence of CDT-1 stabilization. Moreover, our data confirmed a similar regulation in Xenopus egg extracts, emphasizing a conserved coordination of licensing and elongation events during eukaryotic DNA replication by CDC-48/p97.

    Original languageEnglish
    Pages (from-to)85-96
    Number of pages12
    JournalMolecular Cell
    Volume44
    Issue number1
    DOIs
    Publication statusPublished - 7 Oct 2011

    Keywords

    • XENOPUS EGG EXTRACTS
    • UBIQUITIN-SELECTIVE CHAPERONE
    • AAA ATPASE CDC48/P97
    • CAENORHABDITIS-ELEGANS
    • CELL-CYCLE
    • C-ELEGANS
    • S-PHASE
    • PROTEIN-DEGRADATION
    • GENOME STABILITY
    • CDC45

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